tbuckley/cabot-search huggingface dataset:
KLF12 overcomes anti-PD-1 resistance by reducing galectin-1 in cancer cells
Authors: Yujia Zheng, Hao Zhang, Chu Xiao, Ziqin Deng, Tao Fan, Bo Zheng, Chunxiang Li, Jie He
Journal: Journal for ImmunoTherapy of Cancer (2023)

Backgrounds Immune checkpoint blockade has revolutionized cancer treatment and has improved the survival of a subset of patients with cancer. However, numerous patients do not benefit from immunotherapy, and treatment resistance is a major challenge. Krüppel-like factor 12 (KLF12) is a transcriptional inhibitor whose role in tumor immunity is unclear. Methods We demonstrated a relationship between KLF12 and CD8 + T cells in vivo and in vitro by flow cytometry. The role and underlying mechanism that KLF12 regulates CD8 + T cells were investigated using reverse transcription and quantitative PCR, western blot FACS, chromatin immunoprecipitation-PCR and Dual-Luciferase reporter assays, etc, and employing small interfering RNA (siRNA) and inhibitors. In vivo efficacy studies were conducted with multiple mouse tumor models, employing anti-programmed cell death protein 1 combined with KLF12 or galectin-1 (Gal-1) inhibitor. Results Here, we found that the expression of tumor KLF12 correlates with immunotherapy resistance. KLF12 suppresses CD8 + T cells infiltration and function in vitro and in vivo. Mechanistically, KLF12 inhibits the expression of Gal-1 by binding with its promoter, thereby improving the infiltration and function of CD8 + T cells, which plays a vital role in cancer immunotherapy. Conclusions This work identifies a novel pathway regulating CD8 + T-cell intratumoral infiltration, and targeting the KLF12/Gal-1 axis may serve as a novel therapeutic target for patients with immunotherapy resistance.
Corrigendum to “Highly versus less bioavailable oral antibiotics in the treatment of gram-negative bloodstream infections: a propensity-matched cohort analysis” [Clin Microbiol Infect 29(4) (2023 April) 490-497]
Authors: Kwadwo Mponponsuo, Kevin A. Brown, Daniel J. Fridman, Jennie Johnstone, Bradley J. Langford, Samantha M. Lee, Derek R. MacFadden, Samir N. Patel, Kevin L. Schwartz, Nick Daneman
Journal: Clinical Microbiology and Infection (2023)
Bioactive materials for in vivo sweat gland regeneration
Authors: Xinling Yang, Mingchen Xiong, Xiaobing Fu, Xiaoyan Sun
Journal: Bioactive Materials (2023)

Loss of sweat glands (SwGs) commonly associated with extensive skin defects is a leading cause of hyperthermia and heat stroke. In vivo tissue engineering possesses the potential to take use of the body natural ability to regenerate SwGs, making it more conducive to clinical translation. Despite recent advances in regenerative medicine, reconstructing SwG tissue with the same structure and function as native tissue remains challenging. Elucidating the SwG generation mechanism and developing biomaterials for in vivo tissue engineering is essential for understanding and developing in vivo SwG regenerative strategies. Here, we outline the cell biology associated with functional wound healing and the characteristics of bioactive materials. We critically summarize the recent progress in bioactive material-based cell modulation approaches for in vivo SwG regeneration, including the recruitment of endogenous cells to the skin lesion for SwG regeneration and in vivo cellular reprogramming for SwG regeneration. We discussed the re-establishment of microenvironment via bioactive material-mediated regulators. Besides, we offer promising perspectives for directing in situ SwG regeneration via bioactive material-based cell-free strategy, which is a simple and effective approach to regenerate SwG tissue with both fidelity of structure and function. Finally, we discuss the opportunities and challenges of in vivo SwG regeneration in detail. The molecular mechanisms and cell fate modulation of in vivo SwG regeneration will provide further insights into the regeneration of patient-specific SwGs and the development of potential intervention strategies for gland-derived diseases.
Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study
Authors: Alissa M D'Gama, Sarah Mulhern, Beth R Sheidley, Fadil Boodhoo, Sarah Buts, Natalie J Chandler, Joanna Cobb, Meredith Curtis, Edward J Higginbotham, Jonathon Holland, Tayyaba Khan, Julia Koh, Nicole S Y Liang, Lyndsey McRae, Sarah E Nesbitt, Brandon T Oby, Ben Paternoster, Alistair Patton, Graham Rose, Elizabeth Scotchman, Rozalia Valentine, Kimberly N Wiltrout, Robin Z Hayeems, Puneet Jain, Sebastian Lunke, Christian R Marshall, Shira Rockowitz, Neil J Sebire, Zornitza Stark, Susan M White, Lyn S Chitty, J Helen Cross, Ingrid E Scheffer, Vann Chau, Gregory Costain, Annapurna Poduri, Katherine B Howell, Amy McTague
Journal: The Lancet Neurology (2023)
Anal-Sphincter Disruption during Vaginal Delivery
Authors: Abdul H. Sultan, Michael A. Kamm, Christopher N. Hudson, Janice M. Thomas, Clive I. Bartram
Journal: New England Journal of Medicine (1993)

Lacerations of the anal sphincter or injury to sphincter innervation during childbirth are major causes of fecal incontinence, but the incidence and importance of occult sphincter damage during routine vaginal delivery are unknown. We sought to determine the incidence of damage to the anal sphincter and the relation of injury to symptoms, anorectal physiologic function, and the mode of delivery.
Stimulus-guided adaptive transformer network for retinal blood vessel segmentation in fundus images
Authors: Ji Lin, Xingru Huang, Huiyu Zhou, Yaqi Wang, Qianni Zhang
Journal: Medical Image Analysis (2023)

Automated retinal blood vessel segmentation in fundus images provides important evidence to ophthalmologists in coping with prevalent ocular diseases in an efficient and non-invasive way. However, segmenting blood vessels in fundus images is a challenging task, due to the high variety in scale and appearance of blood vessels and the high similarity in visual features between the lesions and retinal vascular. Inspired by the way that the visual cortex adaptively responds to the type of stimulus, we propose a Stimulus-Guided Adaptive Transformer Network (SGAT-Net) for accurate retinal blood vessel segmentation. It entails a Stimulus-Guided Adaptive Module (SGA-Module) that can extract local-global compound features based on inductive bias and self-attention mechanism. Alongside a light-weight residual encoder (ResEncoder) structure capturing the relevant details of appearance, a Stimulus-Guided Adaptive Pooling Transformer (SGAP-Former) is introduced to reweight the maximum and average pooling to enrich the contextual embedding representation while suppressing the redundant information. Moreover, a Stimulus-Guided Adaptive Feature Fusion (SGAFF) module is designed to adaptively emphasize the local details and global context and fuse them in the latent space to adjust the receptive field (RF) based on the task. The evaluation is implemented on the largest fundus image dataset (FIVES) and three popular retinal image datasets (DRIVE, STARE, CHASEDB1). Experimental results show that the proposed method achieves a competitive performance over the other existing method, with a clear advantage in avoiding errors that commonly happen in areas with highly similar visual features. The sourcecode is publicly available at: https://github.com/Gins-07/SGAT.
The effect of a comprehensive typhoid conjugate vaccine campaign on antimicrobial prescribing in children in Harare, Zimbabwe: a mixed methods study
Authors: Ioana D Olaru, Rudo M S Chingono, Christian Bottomley, Faith R Kandiye, Fadzaishe Mhino, Chipo A Nyamayaro, Salome Manyau, Michael Vere, Phillomina Chitando, Prosper Chonzi, Thomas C Darton, Justin Dixon, Katharina Kranzer
Journal: The Lancet Global Health (2023)

BackgroundVaccines prevent infections and could subsequently reduce antimicrobial use. A 1-week mass vaccination campaign was done with Typbar-TCV (Bharat Biotech, Hyderabad, India) between Feb 25 and March 4, 2019. We investigated whether this typhoid conjugate vaccine campaign could affect antimicrobial prescribing in children presenting to primary care in Harare, Zimbabwe.MethodsIn this mixed methods study, data for acute paediatric outpatient consultations between Jan 1, 2018, and March 31, 2020, were collected from five clinics in Harare. Interrupted time series analysis was done to compare prescription data before and after the campaign. To contextualise findings, qualitative data were collected between April 20, 2021, and July 20, 2022, comprising ethnographic research (ie, workshops, surveys, observations, and interviews) in 14 clinics. Ethnographic data were used for thematic analysis. The primary outcome was monthly antimicrobial prescriptions in children aged 6 months to 15 years, normalised by the number of trauma events in all age groups.FindingsIn the data collection period, 27 107 paediatric consultations were recorded. 17 951 (66·2%) of 27 107 children were prescribed antimicrobials. Despite the perceived reduction in typhoid cases and a decreasing trend in the prescription of antimicrobials commonly used to treat typhoid (ie, ciprofloxacin and azithromycin), mass vaccination with Typbar-TCV did not affect the total rate of antimicrobials (adjusted rate ratio, 1·20, 95% CI 0·70–2·05, p=0·51) or the rate of typhoid antimicrobials prescribed (0·93, 0·44–1·96, p=0·85). Unsafe water sources and insufficient diagnostic services were reported to contribute to the continued disease burden and antimicrobial prescription.InterpretationNon-specific febrile illness caused by confirmed or suspected typhoid is a common cause of antimicrobial use in endemic areas. Although effective in preventing typhoid fever, we were unable to identify any effect of Typbar-TCV on antimicrobial prescribing. Ethnographic research showed the effect of contextual factors on antimicrobial prescribing, including concerns regarding safe water access, appropriate sewage disposal, health-care and diagnostic availability. To realise effects beyond disease burden reduction, holistic approaches addressing these concerns are needed so that the value of vaccines mitigating the effects of antimicrobial use as a driver of antimicrobial resistance is fully achieved.FundingWellcome Trust.TranslationFor the Shona translation of the abstract see Supplementary Materials section.
Decreased liver-to-spleen ratio in low-dose computed tomography as a biomarker of fatty liver disease reflects risk for myocardial ischaemia
Authors: A Hokkanen, H Hämäläinen, T M Laitinen, T P Laitinen
Journal:  (2023)

Abstract Aims A strong association between fatty liver disease (FLD) and coronary artery disease is consistently reported. Our aim was to evaluate whether FLD diagnosed using low-dose non-contrast computed tomography (LDCT), as a by-product of myocardial perfusion imaging (MPI), is associated with myocardial ischaemia or left ventricular function parameters. Methods and results We analysed 742 patients who had undergone MPI using single photon emission computed tomography (SPECT) and LDCT. A liver-to-spleen ratio (in Hounsfield units) of &amp;lt;1 was defined as FLD. Myocardial ischaemia was defined as a summed difference score (SDS) ≥3. Left ventricular size and systolic function were assessed from the electrocardiogram-gated SPECT. FLD patients were younger (63 vs. 68 years) and had a higher body mass index (34.6 vs. 29.0 kg/m2) and a higher SDS (2.65 vs. 1.63), P &amp;lt; 0.001 for all. Independently of several possible confounding factors including traditional risk factors, patients with FLD had a 1.70-fold risk of ischaemia (95% confidence interval 1.11–2.58, P = 0.014). Left ventricular end-diastolic volume (109 vs. 109 mL) and ejection fraction (61 vs. 61%) were comparable in those with and without FLD (non-significant for both). Conclusions With the help of LDCT, it is possible to identify FLD, which is associated with an increased risk of myocardial ischaemia. Therefore, evaluation of FLD from LDCT is recommended along with MPI.
P1258: A CO-REACTIVATION MODEL OF DOUBLE-STRANDED DNA VIRUS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WAS CONSTRUCTED TO PREDICT THE MORTALITY AFTER TRANSPLANTATION
Authors: Jinhua Ren, Dabin Chen, Haojie Zhu, Jianda Hu, Ting Yang
Journal: HemaSphere (2023)

Topic: 21. Stem cell transplantation - Experimental Background: Despite significant advances in treatment and prevention, reactivation of double-stranded DNA (dsDNA) viruses often occurs after allo-HSCT, leading to end-organ injury and affecting transplant prognosis. As reported, detecting multiple dsDNA viruses was frequent after allogeneic HSCT and had a dose-dependent association with increased mortality. Aims: The objective of this study was to develop a model for predicting the occurrence of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) co-reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: A total of 373 allo-HSCT patients were enrolled, and the population was randomly divided into a training cohort of 70% (n=261) and a validation cohort of 30% (n=112). The model developed was based on several factors, including CMV and EBV reactivation time, patient age, gender, HbcAb, transplant type, ATG, aGVHD, and cGVHD. Results: The model was as follows: y = -6.21338339 + 0.01923832 × (CMVr time) + 0.00362628 × (EBVr time) - 0.57604523 × (Patient gender) + 0.01974136 × (Patient Age) + 0.85514424 × 9(HbcAb) + 1.13782872 × (Transplant type) + 0.95376138 × (ATG) - 0.62393602 × (aGVHD) - 1.09485262 × (cGVHD). It showed a g-mean value of 0.685 and a probability threshold of 0.297, which allowed for identifying high-risk and low-risk patient groups. The cumulative incidence of the 100-day CMV and EBV co-infection was significantly higher in the high-risk group than in the low-risk group (49.3% [95% confidence interval (CI), 40.6%–56.8%] vs. 16.9% (95% CI, 11.8%–21.6%) (P<0.0001). And were 41.7% (95%CI, 25.9%–54.1%) vs. 17.9% (95% CI, 11.9%–23.4%) (P=0.00026) in the high-risk group than in the low-risk group for the patients with aGVHD. 53% (95%CI, 42.1%–61.8%) vs. 14.0% (95% CI, 4.5%–22.6%) (P<0.0001) in the high-risk group than in the low-risk group for the patients without aGVHD. The model was also able to predict posttransplant mortality and survival. Summary/Conclusion: In conclusion, the model developed in this study provides a comprehensive tool for predicting CMV and EBV co-reactivation after allo-HSCT. Keywords: Cytomegalovirus, Hematopoietic stem cell, Epstein barr virus, High risk
Erratum: “Health Effects of Pesticide Exposure in Latin American and the Caribbean Populations: A Scoping Review”
Authors: Liliana A. Zúñiga-Venegas, Carly Hyland, María Teresa Muñoz-Quezada, Lesliam Quirós-Alcalá, Mariana Butinof, Rafael Buralli, Andres Cardenas, Ricardo A. Fernandez, Claudia Foerster, Nelson Gouveia, Juan P. Gutiérrez Jara, Boris A. Lucero, María Pía Muñoz, Muriel Ramírez-Santana, Anna R. Smith, Noemi Tirado, Berna van Wendel de Joode, Gloria M. Calaf, Alexis J. Handal, Agnes Soares da Silva, Sandra Cortés, Ana M. Mora
Journal: Environmental Health Perspectives (2023)
Bioactive Glasses‐Based Nanozymes Composite Macroporous Cryogel with Antioxidative, Antibacterial, and Pro‐Healing Properties for Diabetic Infected Wound Repair
Authors: Shuangli Zhu, Maocai Li, Zetao Wang, Qi Feng, Huichang Gao, Qingtao Li, Xiaofeng Chen, Xiaodong Cao
Journal: Advanced Healthcare Materials (2023)

The treatment for diabetic ulcers still remains a big clinic challenge owing to the adverse repair microenvironment. Bioactive glasses (BGs) play an important role in the late stages of healing due to their ability to promote vascularization and collagen fiber deposition, but fail to improve infection and oxidative stress in the early stage.Therefore, it is critical to develop a material involved in regulating the whole healing phases. In this work, BGs-based nanozymes (MnO2 @PDA-BGs) with antioxidation, antibacterial and pro-healing abilities are synthesized by the redox deposition of MnO2 on mesoporous BGs. Afterward, cryogel with the interconnected macropore structure is fabricated by the polymerization of methacrylate anhydride gelatin (GelMA) at -20 °C. MnO2 @PDA-BGs are loaded into the cryogel to obtain nanocomposite cryogel (MnO2 @PDA-BGs/Gel) with multiple enzymes-like- activities to eliminate reactive oxygen species (ROS). Besides, MnO2 @PDA-BGs/Gel has intensive peroxidase-like activity under acidic condition and near infrared photothermal responsiveness to achieve excellent antibacterial performance. Cells experiments demonstrate that MnO2 @PDA-BGs/Gel recruits L929s and promotes their proliferation. Furthermore, MnO2 @PDA-BGs/Gel eliminates intracellular overexpressed ROS and maintains the viability of L929s. Animal experiments confirm that MnO2 @PDA-BGs/Gel promotes wound healing and avoided scarring by killing bacteria, reversing inflammation, promoting vascularization, and improving the deposition of collagen III.
Communal interaction of glycation and gut microbes in diabetes mellitus, Alzheimer's disease, and Parkinson's disease pathogenesis
Authors: Rahul Shivaji Patil, Rashmi Santosh Tupe
Journal: Medicinal Research Reviews (2023)

Diabetes and its complications, Alzheimer's disease (AD), and Parkinson's disease (PD) are increasing gradually, reflecting a global threat vis-à-vis expressing the essentiality of a substantial paradigm shift in research and remedial actions. Protein glycation is influenced by several factors, like time, temperature, pH, metal ions, and the half-life of the protein. Surprisingly, most proteins associated with metabolic and neurodegenerative disorders are generally long-lived and hence susceptible to glycation. Remarkably, proteins linked with diabetes, AD, and PD share this characteristic. This modulates protein's structure, aggregation tendency, and toxicity, highlighting renovated attention. Gut microbes and microbial metabolites marked their importance in human health and diseases. Though many scientific shreds of evidence are proposed for possible change and dysbiosis in gut flora in these diseases, very little is known about the mechanisms. Screening and unfolding their functionality in metabolic and neurodegenerative disorders is essential in hunting the gut treasure. Therefore, it is imperative to evaluate the role of glycation as a common link in diabetes and neurodegenerative diseases, which helps to clarify if modulation of nonenzymatic glycation may act as a beneficial therapeutic strategy and gut microbes/metabolites may answer some of the crucial questions. This review briefly emphasizes the common functional attributes of glycation and gut microbes, the possible linkages, and discusses current treatment options and therapeutic challenges.
Diagnostic Performance of the Fibrosis-4 Index and Nonalcoholic Fatty Liver Disease Fibrosis Score in Lean Adults With Nonalcoholic Fatty Liver Disease
Authors: Huiyul Park, Eileen L. Yoon, Takanori Ito, Ae Jeong Jo, Mimi Kim, Jonghyun Lee, Hye-Lin Kim, Taeang Arai, Masanori Atsukawa, Miwa Kawanaka, Hidenori Toyoda, Masatoshi Ishigami, Ming-Lung Yu, Dae Won Jun, Mindie H. Nguyen
Journal: JAMA Network Open (2023)

The diagnostic performance of the fibrosis-4 index (FIB-4) and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) for advanced fibrosis in lean patients with NAFLD is limited.To evaluate the diagnostic performance of the FIB-4 and NFS in lean individuals with NAFLD.This diagnostic study included adults with biopsy-proven NAFLD from 6 referral centers in Asia from 1995 to 2019. Cohorts were matched by age and sex between the lean and nonlean groups. All statistical analyses were executed from October 2022 to March 2023.The diagnostic performance of the FIB-4 and NFS at the current cutoff for advanced hepatic fibrosis in lean (body mass index [BMI] below 23 [calculated as weight in kilograms divided by height in meters squared]) and nonlean (BMI above 23) patients were evaluated.A total of 1501 patients were included in analysis (mean [SD] age, 46.1 [16.4] years); 788 male (52.5%), 115 lean (7.7%), 472 (30.2%) Korean, 821 (48.7%) Japanese, and 341 (21.3%) Taiwanese. Among the age- and sex-matched cohort, the mean (SD) age was 52.3 (15.1) years and 41.2% (47 of 114) were male. The diagnostic performance and areas under the operating characteristic curve of the FIB-4 (lean, 0.807 vs nonlean, 0.743; P = .28) and NFS (lean, 0.790 vs nonlean, 0.755; P = .54) between the 2 groups were comparable in the age- and sex-matched cohort. The sensitivity and specificity of the NFS showed increasing and decreasing tendency according to the BMI quartiles (P for trend < .001), while those of the FIB-4 did not (P for trend = .05 and P = .20, respectively). Additionally, although the areas under the operating characteristic curve of the FIB-4 and NFS were not significantly different in the lean group (0.807 vs 0.790; P = .09), the sensitivity of the current NFS cutoff values was lower in the lean group than in that of FIB-4 (54.4% vs 81.8%; P = .03).In this cohort study, the performance of the FIB-4 and NFS in diagnosing advanced fibrosis did not differ significantly between the 2 groups overall. However, in lean NAFLD, while the sensitivity for diagnosing advanced hepatic fibrosis remained reasonable at the current cutoff level, the sensitivity of NFS at the current cutoff was too low to be an adequate screening tool.
Exploring New Dimensions of Tumor Heterogeneity: The Application of Single Cell Analysis to Organoid‐Based 3D In Vitro Models
Authors: Natalie Landon‐Brace, Nancy T. Li, Alison P. McGuigan
Journal: Advanced Healthcare Materials (2023)

Abstract Modeling the heterogeneity of the tumor microenvironment (TME) in vitro is essential to investigating fundamental cancer biology and developing novel treatment strategies that holistically address the factors affecting tumor progression and therapeutic response. Thus, the development of new tools for both in vitro modeling, such as patient‐derived organoids (PDOs) and complex 3D in vitro models, and single cell omics analysis, such as single‐cell RNA‐sequencing, represents a new frontier for investigating tumor heterogeneity. Specifically, the integration of PDO‐based 3D in vitro models and single cell analysis offers a unique opportunity to explore the intersecting effects of interpatient, microenvironmental, and tumor cell heterogeneity on cell phenotypes in the TME. In this review, the current use of PDOs in complex 3D in vitro models of the TME is discussed and the emerging directions in the development of these models are highlighted. Next, work that has successfully applied single cell analysis to PDO‐based models is examined and important experimental considerations are identified for this approach. Finally, open questions are highlighted that may be amenable to exploration using the integration of PDO‐based models and single cell analysis. Ultimately, such investigations may facilitate the identification of novel therapeutic targets for cancer that address the significant influence of tumor‐TME interactions.